Antitumor dibenzofluorene derivatives

ABSTRACT

Dibenzofluorene derivatives having a formula selected from the group consisting of  
                 
 
     and salts thereof have antitumor activity. At least one of R 1 -R 13  in formula (I) or R 1 -R 12  in formula (II) is —R 14 Z. R 14  is a substituted or unsubstituted amino or amido group having from 1-12 carbon atoms, and Z is a substituted or unsubstituted heterocyclic group having from 1-12 carbon atoms. The remainder of R 1 -R 13  in formula (I) or R 1 -R 12  in formula (II) are independently selected from the group consisting of hydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted amino or amido groups having from 1-12 carbon atoms, and alkyl groups having 1-12 carbon atoms.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to compounds having antitumoractivity. The invention also relates to pharmaceutical compositions thatcontain one or more of those compounds, methods of using the compoundsto inhibit tumor growth in mammals, and methods of preparing thecompounds.

[0002] Many thousands of people are diagnosed with cancer each year, andalthough great advances have been made in cancer therapy, the existingtreatments are not successful in many cases. Among the problems withexisting therapies are (1) anticancer drugs administered to patientsoften have toxic effects on non-cancerous cells in the patient's body,(2) cancerous cells whose growth can be inhibited by certain drugssometimes become resistant to those drugs, and (3) some cancers cannotbe effectively treated with a single drug, and sometimes not even with acombination of different anticancer drugs. A long-standing need existsfor new anticancer drugs that have one or more of the followingcharacteristics: (1) ability to inhibit the growth of cancerous cells,(2) acceptable levels of toxicity to non-cancerous cells, (3)effectiveness against cancerous cells that are resistant to other drugs,and (4) a different mechanism of action than existing drugs, so thatwhen the new drug is used in combination with an existing drug, thelikelihood of the cancer cells developing cross-resistance is reduced.

SUMMARY OF THE INVENTION

[0003] The present invention concerns compounds having a formulaselected from the group consisting of

[0004] or salts thereof. In the above formulas, at least one of R₁-R₁₃in formula (I) or at least one of R₁-R₁₂ in formula (II) is —R₁₄Z. R₁₄is a substituted or unsubstituted amino or amido group preferably havingfrom 1-12 carbon atoms. Z is a substituted or unsubstituted heterocyclicgroup preferably having from 1-12 carbon atoms. The remainder of R₁-R₁₃in formula (I) or R₁-R₁₂ in formula (II) are independently selected fromthe group consisting of hydrogen, hydroxyl, halogen, nitro, substitutedor unsubstituted amino or amido groups preferably having from 1-12carbon atoms, and alkyl groups preferably having from 1-12 carbon atoms.

[0005] As mentioned above, salts of the compounds (I) and (II) are partof the present invention. Examples of suitable salts include but are notlimited to the hydrochloride, iodide, and methane sulfonate salts.

[0006] In one embodiment of the invention where the compound has formulaI, R₁₁ is —R₁₄Z, and R₁-R₁₀ and R₁₂-R₁₃ are independently hydrogen,hydroxyl, halogen, nitro, substituted or unsubstituted amino or amidohaving from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms.

[0007] In another embodiment of the invention where the compound hasformula II, R₁₁ is —R₁₄Z, and R₁-R₁₀ and R₁₂ are independently hydrogen,hydroxyl, halogen, nitro, substituted or unsubstituted amino or amidohaving from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms.

[0008] R₁₄ preferably has the formula —NHR₁₅—, where R₁₅ is asubstituted or unsubstituted aliphatic group having from 2-6 carbonatoms. R₁₅ preferably is selected from the group consisting of—CO(CH₂)_(n)CO—, —(CH₂)_(m)—, and —CO(CH₂)_(q)CHCH(CH₂)_(r)CO—, where n,m, q, and r are independently a number from 0-6. In one preferredembodiment of the invention, n is from 1-4, m is from 2-6, q is from0-2, and r is from 0-2. Z preferably is selected from the groupconsisting of piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, hydroxyethyl piperazinyl, aminoethyl piperazinyl, andaminomethyldihydroxy piperidinyl.

[0009] Another aspect of the present invention is pharmaceuticalcompositions that comprise a compound as described above and apharmaceutically acceptable carrier. Yet another aspect of the presentinvention is a method of inhibiting the growth of tumor cells, in whicha tumor-inhibitory amount of a compound as described above isadministered to a mammal.

[0010] Another aspect of the present invention is a method ofsynthesizing a cyclic hydrocarbon and keto compound. The methodcomprises the step of reacting a cyclic hydrocarbon compound thatcomprises at least two rings with a metal bismuthate in the presence ofan acid. The metal bismuthate can be for example an alkali metalbismuthate such as sodium bismuthate. As another example, it can be zincbismuthate. In certain embodiments of this method, the acid can be anorganic acid such as acetic acid or a mineral acid such as sulfuricacid. Optionally the reaction can take place in the presence of anorganic solvent, such as acetone. The cyclic hydrocarbon reactantpreferably comprises from 10-50 carbon atoms.

[0011] The compounds and compositions of the present invention areuseful in cancer therapy, either by themselves or in combination withother antitumor chemotherapy or radiation therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 depicts a synthesis scheme that is described in Example 1.

[0013] FIGS. 2-4 depict synthesis schemes that are described in Example2.

DESCRIPTION OF SPECIFIC EMBODIMENTS

[0014] Polycyclic aromatic compounds are widely distributed in natureand are considered to be among the significant environmental carcinogens[1]. Previously, considerable research has been directed towards thesynthesis of the polycyclic ring systems [2] and examination of theirmetabolic activation within target cells. Several hypotheses [3] havebeen proposed to establish the correlations between the structure ofthese metabolites, their cellular interactions and carcinogenicity.Eventually, most of the polycyclic metabolic products which act ascarcinogens, intercalate with or bind covalently to DNA. Examination ofseveral frequently used antitumor agents revealed two common structuralfeatures [4]: they have a planar ring system and a basic side chain. Itcould be predicted, therefore, that in addition to other cellularinteractions these compounds would first demonstrate a stronginteraction with the lipid domains of the plasma membranes and othermembranes within the cell [5].

[0015] In some instances, antitumoral, DNA-intercalating drugs have beenshown to interact with cell membranes and in some cases havedemonstrated antitumor activities without further penetrating the cellstructure. This then would put them in a class of drugs that have beencalled generically membrane stabilizing agents (MSA) [6]. These areagents which increase membrane stability against various stressors andoften at higher concentration induce membrane destabilization. Forexample, they may act as anti-hemolytic agents at lower concentrationsand cause hemolysis at higher concentrations. In order to determine theimportance of these primary interactions with the plasma membrane oftumor cells in antitumor effects, we undertook an exploratory syntheticand biological evaluation of unique polycyclic aromatic compounds. Thiswas based on our belief that the potential use of such compounds asantitumor agents has not been systematically explored [7], especiallywhen specific modification is applied to enhance the membraneinteraction as the primary effector of antitumor activity. On thisbasis, we began this systematic analysis by synthesizing a number ofdibenzofluorene derivatives and studied their biological effects invitro on a panel of human tumor cell lines. A number of compounds of thepresent invention have been prepared, and are listed in Table 1. TABLE 1Compound No. Compound Name Tx-37N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′N methyl-piper-azinyl)-butane-1,4-dicarboxiamide Tx-38N-[11′-(13′H-Dibenzo[a,g]-fluorenyl]-4-(1′-piperidin-yl)-butane-1,4-dicarboxiamide Tx-47N-[11′-(13′H-Dibenzo[a,g]-fluorenyl]-4-(4′N methyl-piper-azinyl)-but-2-ene-1,4-dicarboxiamide Tx-48N-[11′-13′H-Dibenzo[a,g]-fluorenyl]-4-(1′-piperidinyl)-but-2-ene-1,4-dicarboxiamide Tx-49N-[11′-(13′H-Dibenzo[a,g]-fluorenyl]-4-(4′N methyl-piper- azinylhydrochloride)-butane-1,4-dicarboxiamide Tx-50N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-one]-4-(4′N methyl-piperazinyl)-butane-1,4-dicarboxiamide Tx-51 N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-one]-4-(1′-piper- idinyl)-butane-1,4-dicarboxiamideTx-66 N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(4′N-methyl-piperazinyl)-butane-1,4-dicarboxiamide Tx-67N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(1′-piperidinyl)-butane-1,4-dicarboxiamide Tx-68N-[2′-(9′H-fluorenyl)]-4-(4′N methyl-piperazinyl)-butane-1,4-dicarboxiamide Tx-69N-[2′-(9′H-fluorenyl)]-4-(1′-piperidinyl)-butane-1,4- dicarboxiamide

[0016] Methods for synthesizing the compounds of the present inventionare described in the examples below. Therapeutic compositions containingthese compounds will preferably also include one or morepharmaceutically acceptable carriers, such as saline solution, and mayalso include one or more pharmaceutically acceptable excipients and/oradditional biologically active substances.

[0017] The compounds of the present invention can be used in methods ofinhibiting the growth of tumor cells in mammals, particularly in humans.Specific human malignancies for which these compounds should be usefulinclude breast, colon, ovarian, and prostate cancers, melanoma,leukemia/lymphomas, and possibly others as well. The compounds areadministered to a mammal in an amount effective to inhibit the growth oftumor cells in the mammal. The administration can suitably be parenteraland by intravenous, intraarterial, intramuscular, intralymphatic,intraperitoneal, subcutaneous, intrapleural, or intrathecal injection.Such administration is preferably repeated on a timed schedule untiltumor regression or disappearance has been achieved, and may be used inconjunction with other forms of tumor therapy such as surgery orchemotherapy with different agents. A compound of the present inventionis preferably administered in a dose that is between approximately 0.01and 100 mg/kg of body weight of the mammalian subject.

[0018] The present invention can be further understood from thefollowing examples.

EXAMPLE 1

[0019] This example relates to synthesis of polycyclic aromatic ketones.

[0020] The oxidizing power of sodium bismuthate in acid media is provedby the facile conversion of bivalent manganese salts to heptavalentmanganese. [8] In comparison to other, common oxidizing agents, the useof this reagent in synthetic organic chemistry has not been extensivelyexplored. Rigby [9] demonstrated the cleavage of vicinal diols and theconversion of acyloins to α-diketones by sodium bismuthate. This reagentwas also used for the oxidation of phenols [10], olefins [11] andα-ketols. [12] Recently, a few other bismuth derivatives were developedfor the oxidation of various functional groups. [13]

[0021] Oxidation of benzylic methylenes to the ketones by DDQ [14], PCC[15], CrO₃ [16], tBuOOH [17], tetrapyridinesilver peroxydisulfate [18]is known in the literature. Recently, Harvey et al [19] reported a newoxidation method with n-BuLi in the presence of molecular oxygen.Although this method is attractive, it has several limitations. Forexample, oxidation of some structurally similar benzylic compounds couldnot be achieved by this method. Dimer formation in strong basic mediawas observed and mixtures of products were formed in some cases. Mostimportantly, extreme precaution has to be taken to get successfulresults as the method requires absolutely dry and inert media.

[0022] We have now oxidized benzylic methylenes to ketones under refluxcondition, using sodium bismuthate in acetic acid. As shown in FIG. 1,commercially available tetralin (1), diphenylmethane (5), 9-10dihydroanthracene (3), dibenzosuberane (9) flourene (7a) and2-nitroflourene (7b) were readily converted to the respective ketones 2,6, 4, 8a, 8b and 10 by sodium bismuthate in acetic acid. We selected twosynthetic compounds, 2,3-benzo fluorene (11) and13H-dibenzo[a,g]fluorene (13) reported by Harvey et al [14] for theoxidation study and produced the ketones 12 and 14 in good yield. Thepresence of acetic acid is required for the completion of the reaction.We found that the progress of the reaction became very slow when carriedout without acetic acid. However, use of 10% sulfuric acid did notchange the reaction time that was observed with acetic acid. In order tokeep the reactants in contact with the oxidizing agent, acetone wasadded as a co-solvent.

[0023] Oxidation of 1, 5, 7, 9, 11 and 13 produced monoketones 2, 6, 8,10, 12, and 14 in 50-90% yield. The presence of the diketone was notobserved in the crude product while compound 3 produced a diketone 4 in72% yield. No side products such as hydroxy, acetates, quinones ordicarboxylic acid were observed during this oxidation.

[0024] The mechanism of the sodium bismuthate induced oxidation is notfirmly established. Oxidation of phenols by sodium bismuthate in neutralaromatic solvent has been shown to proceed by one-electron [10(e)](through a radical intermediate) oxidation. Similar reaction in thepresence of acetic acid as the solvent is believed to occur through atwo-electron [10(f)] (carbonium ion) oxidation process. The suggestedmechanism has a close similarity to the chromic acid [20] mediatedbenzylic oxidation. Thus, we hypothesize that our acid-catalyzed sodiumbismuthate induced oxidation of benzylic methylenes may follow one ofthe processes mentioned above.

[0025] A representative procedure is as follows:

[0026] To the starting methylene compound (20 mmol) in acetic acid (4mL, 50%) and acetone (2 mL), was added sodium bismuthate (80 mmol) andthe mixture was heated to reflux under an argon atmosphere. At the endof reaction as indicated by TLC the mixture was filtered through a padof celite and diluted with water (10 mL). The mixture was extracted withmethylene chloride (3×20 mL). The combined organic layer was washed withsodium bicarbonate solution (3×10 mL, 10%), brine (10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresultant crude product was purified by column chromatography. Allproducts have been characterized through a comparison of mp, TLC and NMRwith authentic compounds.

EXAMPLE 2

[0027] This example concerns synthesis of dibenzofluorene derivatives.

[0028] We have developed a novel oxidation method for the conversion ofbenzylic methylenes to benzylic ketones in polycyclic systems by sodiumbismuthate. Thus, as shown in FIG. 2, pentacyclic dibenzofluorene 101was oxidized to the dibenzofluorenone 102 in good yield.

[0029] We have also shown a facile reduction of the polycyclic aromaticnitro compounds to polycyclic aromatic amines (for example, 3 to 4) bysamarium metal in the presence of catalytic amounts of iodine (see FIG.3).

[0030] Using these two methods, we became interested in examining theanti-tumor effects of structurally complex, angular dibenzofluorene[a,g] polycyclic systems with a very reactive bridged methylene group.We believe that a bridged unit in the polycyclic aromatic system couldplay an important role as this can form cation, anion and radicalintermediates. This example describes the nitration study of the 13-Hdibenzofluorene (101) and structure-activity relationship studies ofseveral 13-unsubstituted and 13-substituted diamides (110, 111 and 112).

[0031] We prepared pentacyclic dibenzo[a,g]fluorene (110) in 20% yieldby following the method reported by Harvey [21]. Functionalization ofbenzene and naphthalene derivatives by electrophilic reaction [22] isroutine organic chemistry. The orientation of the electrophile in suchmonocyclic or bicyclic derivatives is predictable. Similar substitutionreaction in polycyclic aromatic system is extremely difficult and thesite of attack does not follow any known orientation rule. In fact, verylittle is known about the electrophilic substitution reaction inpolycyclic aromatic system [23].

[0032] We planned to link a 4-carbon chain side chain with aheterocyclic base at the end to the aromatic ring through nitrogen [24].Therefore, our task was to prepare amino dibenzofluorene 106 for thesubsequent derivatization. Towards this goal, we reacted the ketone 102with nitric acid in acetic acid under different conditions and failed toget any desired nitro derivative. However, the hydrocarbon 101 produceda single nitro compound 105 with nitric acid-acetic acid at 0-5° C. in80% yield. (See FIG. 2.) The location of the nitro group in the aromaticsystem was determined by nmr spectra. The nmr spectrum (400 MHz) of theknown hydrocarbon 101 was taken. Based on the homonuclear decoupling andCOSY nmr studies, all the protons in 101 were assigned as follows: (400MHz, CDCl₃) δ: 8.81 (d, 1H, J=8.46 Hz, H₇), 8.50 (d, 1H, J=8.68 Hz, H₆),8.02 (d, J=8.22 Hz, H₁), 7.89-7.96 (m, 3H, H₄, H₅, H₁₀), 7.70 and 7.79(2H, ABq, J=8.23 Hz, H₁₁, H₁₂), 7.60-7.65 (m, 1H, H₈), 7.45-7.54 (m, 3H,H₂, H₃, H₉). These assignments were supported by the data reported byJones et al [25]. The nmr spectrum of the nitro compound 105 revealedthe absence of the AB quartet which was present in 101. The spectrum of105 showed a new singlet at δ8.39 and a new doublet at δ8.44 ( J=8.75Hz). We eliminated positions C₁, C₄, C₇ and C₁₀ for the nitro groupbecause of the singlet at δ8.44. The positions C₅, C₆, C₈ and C₉ wereeliminated based on the homonuclear decoupling and COSY experiment. Theregion (δ7.5-7.6) of the hydrocarbon 101 remained unaffected in 105clearly ruled out positions C₂ and C₃ for the nitro group in 105. Weeliminated position C₁₂ because of the downfield doublet at δ8.44. The¹³C nmr spectrum of 105 showed the presence of nine quaternary carbons.The signal at δ123.58 due to the C₁₁ carbon (verified by HETCOR study)was not present in the spectrum of 105. A new peak at δ145.24 appearedbecause of the nitro group. Thus, we assigned C₁₁ as the site of thenitro group in 105 based on extensive nmr study.

[0033] Reduction of the nitro compound 105 to the amino compound 106 wascarried out by Pd—C (10%)-ammonium formate [26], samarium-iodine andPd—C (10%)-hydrazine hydrate [27]. We found hydrazine hydrate and Pd/C(10%) gave the best results.

[0034] Our next task was to prepare the side chains 109 and to couplethem to the amine 106. (See FIG. 4.) The acid 108 was prepared byrefluxing succinic anhydride (107) with piperidine (108a) andN-methylpiperazine (108b). The amine 106 was then condensed with theside chains 109 by mixed anhydride method. [28]

[0035] The desired diamides 110 were isolated by column chromatography.The benzylic methylene group in 110 was oxidized by molecular oxygen[29] to get the ketone 111 which was subsequently reduced to the alcohol112. All new compounds gave satisfactory spectral data.

[0036] The compounds of this example (see FIGS. 2, 3, and 4) correlateto the listing of compounds by Tx number in Table 1 as follows: CompoundCompound Tx No. 110a Tx-38 110b Tx-37 111a Tx-51 111b Tx-50 112a Tx-67112b Tx-66

EXAMPLE 3

[0037] Dibenzofluorene in vitro Cytotoxicity Testing

[0038] Every dibenzofluorene derivative was tested, as will be describedbelow, against six to eight cultured, tumor cell lines of human and/oranimal origin, at least half of which were selected from the NCI panelof test tumors. In each experiment, Adriamycin (ADR) was used as amaximally positive control. Subsequent to our determination that thedibenzofluorene derivative Tx-37 demonstrated consistent, highlypositive effects, it was also included in the panel of test agents inevery experiment where dibenzofluorene derivatives were tested.

[0039] In vitro Cytotoxicity Determinations

[0040] Data are IC₅₀ values (MTT assay) reported as μg/ml for 72 hourscontinuous exposure to the drug. Drugs were prepared in DMSO:PEG300(1:1). Further, dilutions were made in a cell culture medium with fetalbovine serum. Test Tumor Lines BRO human melanoma HT-29 human colonadenocarcinoma P388/0 murine lymphatic leukemia MCF-7 human breastcarcinoma HL-60 human promyelocytic leukemia OVCAR 3 human ovariancarcinoma

[0041] Additional tumor lines against which the drugs were tested incertain series included L1210 (leukemia), PC3 (prostate) and severalothers.

[0042] Compounds were evaluated for solubility characteristics invehicles which would be appropriate for use in cell culture. Thecompounds were added to the cell lines under continuous culture for 72hours. Inhibition of growth relative to control cell culture wasdetermined by the MTT method at the end of 72 hours. This is a test ofthe relative ability of a compound to inhibit cell growth not survival.However, inhibition of growth may reflect cell death and/or cytostasis.

[0043] Summarized results of the in vitro cytotoxicity testing,specifically average IC₅₀ values for the various tumor lines, are givenin Table 2. TABLE 2 # Agent Runs P388/0 BRO HT-29 MCF-7 OVCAR-3 HL-60Tx-37 5 2.0 1.8 1.9 3.0 1.9 1.6 Tx-38 3 42.9 46.4 34.4 22.8 39.5 14.9Tx-47 1 15.4 1.2 16.7 20.2 1.1 1.2 Tx-48 1 71.5 22.6 52.2 18.3 23.4 30.1Tx-49 1 3.1 2.5 2.5 5.7 2.8 2.5 Tx-50 2 3.7 11.2 10.0 18.1 6.6 4.0 Tx-511 55.4 47.2 65.1 27.0 16.2 32.0 Tx-66 1 2.1 6.0 5.9 4.2 2.0 Tx-67 1 9.214.7 8.9 8.8 5.6 Tx-68 1 41.7 18.2 31.7 Tx-69 1 41.5 28.9 52.6

[0044] An IC₅₀ value above 50 μg/ml indicates that there wasinsufficient cytotoxicity of the compound to achieve a 50% inhibition ofcell growth at 50 μg/ml. In some cases, we observed cytotoxicity at 100μg/ml but few of the drugs are readily soluble at this concentration andthe data are not reliable.

[0045] ADR invariably produced the described anti-tumor effect againstall tumor lines at concentrations lower than 1 μg/ml of culture media.The effect of the Tx-compounds was divided into five activity groups asdescribed below. In all cases, if activity against a single tumor linediffered radically from that against all others, notation was made ofthis specificity but the agent was grouped as determined by the majorityof the results.

[0046] Group A. These agents were effective against all tumor lines atconcentrations under 5 μg/ml. Some of these compounds were effective atless than 1 log difference from the activity of ADR.

[0047] Group B. These agents were effective against all tumor lines atless than 10 μg/ml.

[0048] Group C. These agents were effective against one-third toone-half of all tumor lines tested at levels less than 10 μg/ml.

[0049] Group D. These agents were effective against one or two of thesix to eight tumor lines tested at concentrations of less than 10 μg/ml.

[0050] Group E. These agents produced some anti-tumor effect at dosesabove 10 μg/ml but less than 20 μg/ml.

[0051] Group F. These agents were “effective” against some tumor linesabove 20 μg/ml but often demonstrated no anti-tumor effect. TABLE 3GROUP A Tx-37 Tx-49 Tx-66 GROUP B Tx-50 Tx-67 GROUP C Tx-47 GROUP ETx-68 GROUP F Tx-38 Tx-51 Tx-48 Tx-69

[0052] In summary of these findings, the most active compound producedin this series was Tx-37, the dibenzofluorene molecule with a terminalN-methyl piperazine heterocyclic ring. While the hydrochloride salt(Tx-49) or the addition of a hydroxyl moiety at position 13 (Tx-66),produced minor change in the activity, the substitution of a ketonemoiety at position 13 (Tx-50) produced a slight diminution in activity.The insertion of an unsaturated bond in the alkyl chain at Tx-37 (Tx-47)reduced its activity significantly.

[0053] Tx-38 with a terminal piperidine heterocyclic ring demonstratedno significant anti-tumor activity and the insertion of an unsaturatedbond in this molecule produced little or no change (Tx-48). However, theaddition of the hydroxyl moiety at position 13, which caused minorchange in Tx-37, greatly increased the activity of Tx-38 (Tx-67).

[0054] As we have reported in other compounds based on other polycyclicring structures, those that terminate in a N-methyl piperazine ringagain demonstrated far greater activity than those that terminated in apiperidine ring. Thus, Tx-38 and Tx-51 possess little or no activitywhen compared with the significant activities of Tx-37 and Tx-50 againstall tumor lines. Modification of other components of the molecule,however, such as insertion of the hydroxyl moiety at position 13 ofTx-38 (Tx-67) often reduced or eliminated these differences; in thiscase by greatly enhancing its activity.

[0055] The preceding description of specific embodiments of the presentinvention is not intended to be a complete list of every possibleembodiment of the invention. Persons skilled in this field willrecognize that modifications can be made to the specific embodimentsdescribed here that would be within the scope of the present invention.

[0056] References

[0057] The following references, to the extent that they provideexemplary procedural or other details supplementary to those set forthherein, are specifically incorporated herein by reference.

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[0081] [22] Ranu, B. C.; Ghosh, K. Jana, U. J. Org Chem. 1996, 61, 9546and references cited therein.

[0082] [23] Minabe, M.; Cho, B. P.; Harvey, R. V. J. Am. Chem. Soc.1989, 111, 3809.

[0083] [24] Palmer, B. D.; Lee, H. H; Baguley, B. C.: Denny, W. A. J.Med. Chem. 1992, 35, 258.

[0084] [25] Jones, D. W.; Matthews, R. S.; Bartle, K. D. SpectrochimActa, Part A, 1972, 28, 2053.

[0085] [26] Bose, A. K.; Banik, B. K.; Barakat, K. J.; Manhas, M. S.Synlett, 1993, 575.

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[0087] [28] Holzapfel, C. W.; Pettit, G. R. J. Org. Chem. 1985, 50,2323.

[0088] [29] Harvey, R. G.; Abu-Shqara, E.; Yang, C. X. J. Org. Chem.1992, 57, 6313.

What is claimed is:
 1. A compound having a formula selected from thegroup consisting of

or a salt thereof, where at least one of R₁-R₁₃ in formula (I) or atleast one of R₁-R₁₂ in formula (II) is —R₁₄Z, where R14 is a substitutedor unsubstituted amino or amido group having from 1-12 carbon atoms, andZ is a substituted or unsubstituted heterocyclic group having from 1-12carbon atoms; where the remainder of R₁-R₁₃ in formula (I) or R₁-R₁₂ informula (II) are independently selected from the group consisting ofhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, and alkyl groups having1-12 carbon atoms.
 2. The compound of claim 1, where the compound hasformula I, R₁₁ is —R₁₄Z, and R₁-R₁₀ and R₁₂-R₁₃ are independentlyhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, or alkyl having 1 -1 12carbon atoms.
 3. The compound of claim 1, where the compound has formulaII, R₁₁ is —R₁₄Z, and R₁-R₁₀ and R₁₂ are independently hydrogen,hydroxyl, halogen, nitro, substituted or unsubstituted amino or amidogroups having from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms.4. The compound of claim 1, where R₁₄ has the formula —NHR₁₅—, where R₁₅is a substituted or unsubstituted aliphatic group having from 2-6 carbonatoms.
 5. The compound of claim 4, where R₁₅ is selected from the groupconsisting of —CO(CH₂)_(n)CO—, —(CH₂)_(m)—, and—CO(CH₂)_(q)CHCH(CH₂)_(r)CO—, where n is from 1-4, m is from 2-6, q isfrom 0-2, and r is from 0-2.
 6. The compound of claim 1, where Z isselected from the group consisting of piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, hydroxyethyl piperazinyl,aminoethyl piperazinyl, and aminomethyldihydroxy piperidinyl.
 7. Thecompound of claim 1, where the compound is selected from the groupconsisting of: N-[11′-(13 ′H-Dibenzo[a,g]-fluorenyl)]-4-(4′Nmethyl-piperazinyl)-butane-1,4-dicarboxiamide;N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′N methyl-piperazinylhydrochloride)-butane-1,4-dicarboxiamide; andN-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(4′N-methyl-piperazinyl)-butane-1,4-dicarboxiamide.8. The compound of claim 1, where the compound is selected from thegroup consisting of: N-[11′-(13′H-Dibenzo [a,g]-fluorene-13′-one]-4-(4′Nmethyl-piperazinyl)-butane-1,4-dicarboxiamide; andN-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(1′-piperidinyl)-butane-1,4-dicarboxiamide.9. A compound having a formula selected from the group consisting of

or a salt thereof; where R₁-R₁₀, R₁₂, and R₁₃ if the compound hasformula (I), are independently selected from the group consisting ofhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, and alkyl groups having1-12 carbon atoms; where R₁₁ is —R₁₄Z; where R₁₄ has the formula—NHR₁₅—, where R₁₅ is a substituted or unsubstituted aliphatic grouphaving from 2-6 carbon atoms; and where Z is a substituted orunsubstituted heterocyclic group having from 1-12 carbon atoms.
 10. Apharmaceutical composition, comprising: (a) a compound having a formulaselected from the group consisting of

or a salt thereof, where at least one of R₁-R₁₃ in formula (I) or atleast one of R₁-R₁₂ in formula (II) is —R₁₄Z, where R₁₄ is a substitutedor unsubstituted amino or amido group having from 1-12 carbon atoms, andZ is a substituted or unsubstituted heterocyclic group having from 1-12carbon atoms; where the remainder of R₁-R₁₃ in formula (I) or R₁-R₁₂ informula (II) are independently selected from the group consisting ofhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, and alkyl groups havingfrom 1-12 carbon atoms; and (b) a pharmaceutically acceptable carrier.11. The composition of claim 10, where the compound has formula I, R₁₁is —R₁₄Z, and R₁-R₁₀ and R₁₂-R₁₃ are independently hydrogen, hydroxyl,halogen, nitro, substituted or unsubstituted amino or amido groupshaving from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms. 12.The composition of claim 10, where the compound has formula II, R₁₁ is—R₁₄Z, and R₁-R₁₀ and R₁₂ are independently hydrogen, hydroxyl, halogen,nitro, substituted or unsubstituted amino or amido groups having from1-12 carbon atoms, or alkyl having 1-12 carbon atoms.
 13. Thecomposition of claim 10, where R₁₄ has the formula —NHR₁₅—, where R₁₅ isa substituted or unsubstituted aliphatic group having from 2-6 carbonatoms.
 14. The composition of claim 13, where R₁₅ is selected from thegroup consisting of —CO(CH₂)_(n)CO—, —(CH₂)_(m)—, and—CO(CH₂)_(q)CHCH(CH₂)_(r)CO—, where n is from 1-4, m is from 2-6, q isfrom 0-2, and r is from 0-2.
 15. The composition of claim 10, where Z isselected from the group consisting of piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, hydroxyethyl piperazinyl,aminoethyl piperazinyl, and aminomethyldihydroxy piperidinyl.
 16. Thecomposition of claim 10, where the compound is selected from the groupconsisting of: N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′Nmethyl-piperazinyl)-butane-1,4-dicarboxiamide;N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′N methyl-piperazinylhydrochloride)-butane-1,4-dicarboxiamide; andN-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(4′N-methyl-piperazinyl)-butane-1,4-dicarboxiamide.17. The composition of claim 10, where the compound is selected from thegroup consisting of: N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-one]-4-(4′Nmethyl-piperazinyl)-butane-1,4-dicarboxiamide; andN-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(1′-piperidinyl)-butane-1,4-dicarboxiamide.18. A pharmaceutical composition, comprising: (a) a compound having aformula selected from the group consisting of

or a salt thereof; where R₁-R₁₀, R₁₂, and R₁₃ if the compound hasformula (I), are independently selected from the group consisting ofhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, and alkyl groups having1-12 carbon atoms; where R₁₁ is —R₁₄Z; where R₁₄ has the formula—NHR₁₅—, where R₁₅ is a substituted or unsubstituted aliphatic grouphaving from 2-6 carbon atoms; and where Z is a substituted orunsubstituted heterocyclic group having from 1-12 carbon atoms; and (b)a pharmaceutically acceptable carrier.
 19. A method of inhibiting thegrowth of tumor cells, comprising the step of administering to a mammalan amount effective to inhibit tumor cell growth of a compound having aformula selected from the group consisting of

or a salt thereof; where at least one of R₁-R₁₃ in formula (I) or atleast one of R₁-R₁₂ in formula (II) is —R₁₄Z, where R₁₄ is a substitutedor unsubstituted amino or amido group having from 1-12 carbon atoms, andZ is a substituted or unsubstituted heterocyclic group having from 1-12carbon atoms; and where the remainder of R₁-R₁₃ in formula (I) or R₁-R₁₂in formula (II) are independently selected from the group consisting ofhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, and alkyl groups havingfrom 1-12 carbon atoms.
 20. The method of claim 19, where the compoundhas formula I, R₁₁ is —R₁₄Z, and R₁-R₁₀ and R₁₂-R₁₃ are independentlyhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, or alkyl having 1-12carbon atoms.
 21. The method of claim 19, where the compound has formulaII, R₁₁ is —R₁₄Z, and R₁-R₁₀ and R₁₂ are independently hydrogen,hydroxyl, halogen, nitro, substituted or unsubstituted amino or amidogroups having from 1-12 carbon atoms, or alkyl having 1-12 carbon atoms.22. The method of claim 19, where R₁₄ has the formula —NHR₁₅—, where R₁₅is a substituted or unsubstituted aliphatic group having from 2-6 carbonatoms.
 23. The method of claim 22, where R₁₅ is selected from the groupconsisting of —CO(CH₂)_(n)CO—, —(CH₂)_(m)—, and—CO(CH₂)_(q)CHCH(CH₂)_(r)CO—, where n is from 1-4, m is from 2-6, q isfrom 0-2, and r is from 0-2.
 24. The method of claim 19, where Z isselected from the group consisting of piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, hydroxyethyl piperazinyl,aminoethyl piperazinyl, and aminomethyldihydroxy piperidinyl.
 25. Themethod of claim 19, where the compound is selected from the groupconsisting of: N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′Nmethyl-piperazinyl)-butane-1,4-dicarboxiamide;N-[11′-(13′H-Dibenzo[a,g]-fluorenyl)]-4-(4′N methyl-piperazinylhydrochloride)-butane-1,4-dicarboxiamide; andN-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(4′N-methyl-piperazinyl)-butane-1,4-dicarboxiamide.26. The method of claim 19, where the compound is selected from thegroup consisting of: N-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-one]-4-(4′Nmethyl-piperazinyl)-butane-1,4-dicarboxiamide; andN-[11′-(13′H-Dibenzo[a,g]-fluorene-13′-hydroxy]-4-(1′-piperidinyl)-butane-1,4-dicarboxiamide.27. A method of inhibiting the growth of tumor cells, comprising thestep of administering to a mammal an amount effective to inhibit tumorcell growth of a compound having a formula selected from the groupconsisting of

or a salt thereof; where R₁-R₁₀, R₁₂, and R₁₃ if the compound hasformula (I), are independently selected from the group consisting ofhydrogen, hydroxyl, halogen, nitro, substituted or unsubstituted aminoor amido groups having from 1-12 carbon atoms, and alkyl groups having1-12 carbon atoms; where R₁₁ is —R₁₄Z; where R₁₄ has the formula—NHR₁₅—, where R₁₅ is a substituted or unsubstituted aliphatic grouphaving from 2-6 carbon atoms; and where Z is a substituted orunsubstituted heterocyclic group having from 1-12 carbon atoms.
 28. Amethod of synthesizing a cyclic ketone compound, comprising the step ofreacting a cyclic hydrocarbon compound that comprises at least two ringswith a metal bismuthate in the presence of an acid.
 29. The method ofclaim 28, where the acid is acetic acid.
 30. The method of claim 28,where the acid is sulfuric acid.
 31. The method of claim 28, where thereaction takes place in the presence of an organic solvent.
 32. Themethod of claim 30, where the organic solvent is acetone.
 33. The methodof claim 28, where the cyclic hydrocarbon compound comprises from 10-50carbon atoms.